The objective of this proposal is to better understand the physiological and molecular mechanisms at work in the Roux-en-Y gastric bypass (RYGB) surgery mediated rapid reversal of the hyperglycemia associated with insulin resistance, prediabetes and T2DM. We propose a novel series of studies focused on the study of a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by dopamine (DA) stored in cell vesicles and the gut. We provide evidence that dopamine (DA) and Glucagon like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that DA represents the anti incretin hypothesized to explain the beneficial effects of bariatric surgery on T2DM. We propose to study these putative circuits using minimally invasive molecular imaging techniques in an animal model. Concurrently, we will characterize dopamine metabolism in the gut and pancreas under fasting and meal stimulated conditions, including a limited human clinical study of dopamine metabolism in a population of patients who have undergone RYGB surgery. The new information obtained from this hypothesis driven research may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery, and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, our studies may result in the development of novels methods to quantitatively asses in real time by imaging both beta cell function as well as mass. Such methods may have clinical application in the treatment and management of diabetes and/or for vetting new drugs aimed preserving or restoring beta cell function and mass in disease.